ArticleCirculation. Cardiovascular genetics2014
A mouse model of human congenital heart disease: high incidence of diverse cardiac anomalies and ventricular noncompaction produced by heterozygous Nkx2-5 homeodomain missense mutation.
Article in Circulation. Cardiovascular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 49 citations in OpenAlex.
- BubR1 Controls Heart Development by Promoting Expression of Cardiogenesis Regulators.Journal of the American Heart Association · 2025Article
- Molecular Pathways and Animal Models of Ebstein's Anomaly.Advances in experimental medicine and biology · 2024Review
- Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1.Circulation research · 2023Article
- Article
- A Systematic Review of Ebstein's Anomaly with Left Ventricular Noncompaction.Journal of cardiovascular development and disease · 2022Review
- Splicing factor Srsf5 deletion disrupts alternative splicing and causes noncompaction of ventricular myocardium.iScience · 2021Article
- Genetics of congenital heart disease: a narrative review of recent advances and clinical implications.Translational pediatrics · 2021Review
- An eIF3a gene mutation dysregulates myocardium growth with left ventricular noncompaction via the p-ERK1/2 pathway.Genes & diseases · 2021Article
- In Vivo and In Vitro Genetic Models of Congenital Heart Disease.Cold Spring Harbor perspectives in biology · 2021Review
- Gestational intermittent hyperoxia rescues murine genetic congenital heart disease in part.Scientific reports · 2021Article
- Atrial and Sinoatrial Node Development in the Zebrafish Heart.Journal of cardiovascular development and disease · 2021Review
- Generation of Transgenic Mice that Conditionally Overexpress Tenascin-C.Frontiers in immunology · 2021Article
- Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network.Nature communications · 2020Article
- Moderate hypothermia induces protection against hypoxia/reoxygenation injury by enhancing SUMOylation in cardiomyocytes.Molecular medicine reports · 2020Article
- Extracellular Matrix Disparities in anFrontiers in cardiovascular medicine · 2020Article
- Defects in Trabecular Development Contribute to Left Ventricular Noncompaction.Pediatric cardiology · 2019Review
- Editorial: Genetic Modification of Cardiac Tissue.Frontiers in cardiovascular medicine · 2019Article
- Furin, a transcriptional target of NKX2-5, has an essential role in heart development and function.PloS one · 2019Article
- Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association.Circulation · 2018Review
- Semi-automatic detection of myocardial trabeculation using cardiovascular magnetic resonance: correlation with histology and reproducibility in a mouse model of non-compaction.Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance · 2018Article
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13 authors at 2 institutions in 1 country.
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Abstract
backgroundHeterozygous human mutations of NKX2-5 are highly penetrant and associated with varied congenital heart defects. The heterozygous knockout of murine Nkx2-5, in contrast, manifests less profound cardiac malformations, with low disease penetrance. We sought to study this apparent discrepancy between human and mouse genetics. Because missense mutations in the NKX2-5 homeodomain (DNA-binding domain) are the most frequently reported type of human mutation, we replicated this genetic defect in a murine knockin model. METHODS AND
resultsWe generated a murine model in a 129/Sv genetic background by knocking-in an Nkx2-5 homeodomain missense mutation previously identified in humans. The mutation was located at homeodomain position 52Arg→Gly (R52G). All the heterozygous neonatal Nkx2-5(+/R52G) mice demonstrated a prominent trabecular layer in the ventricular wall, so called noncompaction, along with diverse cardiac anomalies, including atrioventricular septal defects, Ebstein malformation of the tricuspid valve, and perimembranous and muscular ventricular septal defects. In addition, P10 Nkx2-5(+/R52G) mice demonstrated atrial sepal anomalies, with significant increase in the size of the interatrial communication and fossa ovalis, and decrease in the length of the flap valve compared with control Nkx2-5(+/+) or Nkx2-5(+/-) mice.
conclusionsThe results of our study demonstrate that heterozygous missense mutation in the murine Nkx2-5 homeodomain (R52G) is highly penetrant and result in pleiotropic cardiac effects. Thus, in contrast to heterozygous Nkx2-5 knockout mice, the effects of the heterozygous knockin mimic findings in humans with heterozygous missense mutation in NKX2-5 homeodomain.
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